N-substituted-hexahydro-1,2,5-triazepines

Abstract

Disclosed herein are N-substituted-hexahydro-1,2,5-triazepines of formula I, which is ##STR1## or a pharmaceutically acceptable acid addition salt thereof, wherein R 4 and R 5 are independently hydrogen or C 1 -C 4 alkyl; R 1 is (R 6 ) 2 --CH--(CH 2 ) n -- in which n is 0, 1, 2 or 3 and R 6 is p-fluoro, chloro or methoxyphenyl; and R 3 is hydrogen and R 2 is benzoyl, 2,6-dimethyl or diethylbenzoyl, 2,6-dichlorobenzoyl, N-methyl, ethyl or propylcarboxamido, N-phenylcarboxamido, N-2,6-dimethyl or diethylphenylcarboxamido, N-2,6-dichlorophenylcarboxamido, N-methyl, ethyl or propylacetamido, N-phenylacetamido, N-2,6-dimethyl or diethylphenylacetamido, or N-2,6-dichlorophenylacetamido or R 2 and R 3 are the same and are N-methyl, ethyl or propylcarboxamido, benzoyl, 2,6-dimethyl or diethlbenzoyl, 2,6-dichlorobenzoyl, benzyl, 2,6-dimethyl or diethlbenzoyl, 2,6-dichlorobenzoyl, or a removable amino protective group. Also disclosed are N-substituted-hexahydro-1,2,5-triazepines of formula II in which R 1 of formula I is replaced by R 7 which is C 1 -C 4 alkyl, and R 2 and R 3 of formula I are replaced by R 8 and R 9 which are, respectively, N-2,6-dimethyl, diethyl or dichlorophenylcarboxamido or N-2,6-dimethyl, diethyl or dichlorophenylacetamido and hydrogen. The compounds of the invention have antiarrhythmic properties or are intermediates for the preparation thereof.

What is claimed is: 
     
       1. A compound of the formula ##STR5## or a pharmaceutically acceptable acid addition salt thereof, wherein R 4  and R 5  are independently hydrogen or C 1  -C 4  alkyl; R 1  is (R 6 ) 2  --CH--(CH 2 ) n  -- in which n is 0, 1, 2 or 3 and R 6  is p-fluoro, chloro or methoxyphenyl; and   R 3  is hydrogen and R 2  is benzoyl, 2,6-dimethyl or diethylbenzoyl, 2,6-dichlorobenzoyl, N-methyl, ethyl or propylcarboxamido, N-phenylcarboxamido, N-2,6-dimethyl or diethylphenylcarboxamido, N-2,6-dichlorophenylcarboxamido, N-methyl, ethyl or propylacetamido, N-phenylacetamido, N-2,6-dimethyl or diethylphenyl-acetamido, or N-2,6-dichlorophenylacetamido; or   R 2  and R 3  are the same and are N-methyl, ethyl or propylcarboxamido, benzoyl, 2,6-dimethyl or diethylbenzoyl, 2,6-dichlorobenzoyl, benzyl, 2,6-dimethyl or diethylbenzyl, 2,6-dichlorobenzoyl, or a removable amino protective group.   
     
     
       2. A compound of claim 1 in which R 4  and R 5  are independently hydrogen or methyl. 
     
     
       3. A compound of claim 1 in which R 4  and R 5  are hydrogen. 
     
     
       4. A compound of claim 1 in which n in R 1  is 3. 
     
     
       5. A compound of claim 1 in which R 6  in R 1  is p-fluorophenyl. 
     
     
       6. A compound of claim 1 in which R 3  is hydrogen and R 2  is N-methylcarboxamido, N-ethylcarboxamido, 2,6-dimethylbenzyl, N-phenylcarboxamide, N-2,6-dimethylphenylcarboxamido, N-methylacetamido, N-phenylacetamido, or N-2,6-dimethylphenylacetamido. 
     
     
       7. A compound of claim 1 in which R 3  is hydrogen and R 2  is N-phenylcarboxamido, N-2,6-dimethylphenylcarboxamido, benzoyl or N-2,6-dimethylphenylacetamido. 
     
     
       8. A compound of claim 1 in which R 2  and R 3  are the same and are benzoyl or benzyl. 
     
     
       9. A compound of claim 1 in which the removable amino protective group comprising R 2  and R 3  is selected from a group comprising C 1  -C 6  alkanoyl, halo or dihalo (C 1  -C 6 )alkanoyl, pyridinoyl, t-butyloxycarbonyl, trichloroacetyl, C 1  -C 6  alkoxycarbonyl and p-methoxybenzyl. 
     
     
       10. A compound of claim 1 selected from the group comprising 1,2-dibenzoyl-5-[4,4-bis(4-fluorophenyl)butyl]-hexahydro-1H-1,2,5-triazepine and 5-[4,4-bis(4-fluorophenyl)butyl]-hexahydro-1,2-bis(phenylmethyl)-1H-1,2,5-triazepine. 
     
     
       11. A compound of claim 1 which is 5-[4,4-bis(4-fluorophenyl)butyl]-N-ethylhexahydro-1H-1,2,5-triazepine-1-carboxamido or a pharmaceutically acceptable acid addition salt thereof. 
     
     
       12. A compound of claim 1 which is 5-[4,4-bis(4-fluorophenyl)butyl]-N,N'-diethyl-4,5,6,7-tetrahydro-1H-1,2,5-triazepine-1,2(3H)-dicarboxamido or a pharmaceutically acceptable acid addition salt thereof. 
     
     
       13. A compound of claim 1 which is 5-[4,4-bis(4-fluorophenyl)butyl]-hexahydro-N-phenyl-1H-1,2,5-triazepine-1-carboxamido or a pharmaceutically acceptable acid addition salt thereof. 
     
     
       14. A compound of claim 1 which is 5-[4,4-bis(4-fluorophenyl)butyl]-N-(2,6-dimethylphenyl)hexahydro-1H-1,2,5-triazepine-1-carboxamide or a pharmaceutically acceptable acid addition salt thereof. 
     
     
       15. A compound of claim 1 which is 1-benzoyl-5-[4,4-bis(4-fluorophenyl)butyl]hexahydro-1H-1,2,5-triazepine or a pharmaceutically acceptable acid addition salt thereof. 
     
     
       16. A compound of claim 1 which is 5-[4,4-bis(4-fluorophenyl)butyl]-N-2,6-(dimethylphenyl)hexahydro-1H-1,2,5-triazepine-1-acetamido or a pharmaceutically acceptable acid addition salt thereof. 
     
     
       17. A compound of the formula ##STR6## or a pharmaceutically acceptable acid addition salt thereof, wherein R 4  and R 5  are independently hydrogen or C 1  -C 4  alkyl; R 7  is C 1  -C 4  alkyl; and   R 9  is hydrogen and R 8  is N-2,6-dimethyl, diethyl or dichlorophenylcarboxamido or N-2,6-dimethyl, diethyl or dichlorophenylacetamido.   
     
     
       18. A compound of claim 17 in which R 4  and R 5  are hydrogen or methyl. 
     
     
       19. A compound of claim 17 in which R 5  and R 5  are hydrogen. 
     
     
       20. A compound of claim 17 in which R 7  is methyl or ethyl. 
     
     
       21. A compound of claim 17 in which R 9  is hydrogen and R 8  is N-2,6-dimethyl or diethylphenylcarboxamido. 
     
     
       22. A compound of claim 17 which is N-(2,6-dimethylphenyl)hexahydro-5-methyl-1H-1,2,5-triazepine-1-carboxamide. 
     
     
       23. A compound of claim 17 which is N-(2,6-dimethylphenyl)hexahydro-5-ethyl-1H-1,2,5-triazepine-1-carboxamide.